As interventions that affect the course of Alzheimer's disease (AD) become available, it will be more important to diagnose AD at its earliest stages. The goal of this project is to identify, using functional magnetic resonance imaging (fMRI), changes in cerebral physiology occurring in the pre-symptomatic phase of AD by studying persons with Presenilin-1 (PS1) mutations giving rise to autosomal dominant AD. As a career development award another goal is to train the principal investigator in the design, implementation, and interpretation of fMRI experiments. The specific aims are: 1) To establish if there are changes in the pattern of cerebral activity associated with episodic memory detectable on fMRI prior to overt decline in cognitive function in persons destined to develop PSI-related AD, 2) To establish if there are changes on fMRI in the pattern of cerebral activity associated with a test of executive function in this population, and 3) To determine if these changes occur as early as young adulthood. We will compare blood oxygen level dependent fMRI measures between 24 PS1 mutation carriers and 24 non-carriers during performance of two memory tasks and a test of executive function. The subjects will be pre-symptomatic at-risk members of 6 Mexican families with PS1 mutations determinant for early-onset AD. Subjects will undergo genetic testing, 3 hours of cognitive testing, and fMRI scanning over two days. The memory tasks will consist of: 1) a auditory paired-associate word memory test, and a 2) a semantic encoding task followed by a recognition test. A test of executive function will also be given in which subjects repress a natural button-press response on some trials. Analyses will include both within-subjects comparisons of regions of interest and group-averaged statistical parametric mapping comparisons. FMRI measures will also be compared between PS1 mutation carriers and non-carriers in young and older age groups. The lead researcher has fellowship training in dementia and seeks to become independent in cognitive research, including functional neuroimaging modalities such as fMRI. This award will allow time for the research and necessary classes in functional imaging, statistics, and cognitive science. UCI, with its strong dementia research program, growing MRI capabilities and opportunity to collaborate at the nearby UCLA Brain Imaging Center, is an excellent environment for this endeavor.